rs32209

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001999.4(FBN2):ā€‹c.6931A>Gā€‹(p.Met2311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,694 control chromosomes in the GnomAD database, including 12,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.12 ( 2077 hom., cov: 33)
Exomes š‘“: 0.071 ( 10631 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

2
15

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.82
Variant links:
Genes affected
FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
BP4
Computational evidence support a benign effect (MetaRNN=1.4686584E-4).
BP6
Variant 5-128286799-T-C is Benign according to our data. Variant chr5-128286799-T-C is described in ClinVar as [Benign]. Clinvar id is 129046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128286799-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBN2NM_001999.4 linkuse as main transcriptc.6931A>G p.Met2311Val missense_variant 55/65 ENST00000262464.9
FBN2XM_017009228.3 linkuse as main transcriptc.6778A>G p.Met2260Val missense_variant 54/64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBN2ENST00000262464.9 linkuse as main transcriptc.6931A>G p.Met2311Val missense_variant 55/651 NM_001999.4 P1P35556-1
FBN2ENST00000703783.1 linkuse as main transcriptn.3715A>G non_coding_transcript_exon_variant 30/38

Frequencies

GnomAD3 genomes
AF:
0.117
AC:
17723
AN:
152100
Hom.:
2074
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.214
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0674
Gnomad ASJ
AF:
0.0516
Gnomad EAS
AF:
0.602
Gnomad SAS
AF:
0.150
Gnomad FIN
AF:
0.0499
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0456
Gnomad OTH
AF:
0.0875
GnomAD3 exomes
AF:
0.112
AC:
28018
AN:
251276
Hom.:
4642
AF XY:
0.109
AC XY:
14771
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.216
Gnomad AMR exome
AF:
0.0409
Gnomad ASJ exome
AF:
0.0564
Gnomad EAS exome
AF:
0.630
Gnomad SAS exome
AF:
0.138
Gnomad FIN exome
AF:
0.0525
Gnomad NFE exome
AF:
0.0453
Gnomad OTH exome
AF:
0.0722
GnomAD4 exome
AF:
0.0707
AC:
103374
AN:
1461476
Hom.:
10631
Cov.:
32
AF XY:
0.0718
AC XY:
52216
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.214
Gnomad4 AMR exome
AF:
0.0418
Gnomad4 ASJ exome
AF:
0.0579
Gnomad4 EAS exome
AF:
0.602
Gnomad4 SAS exome
AF:
0.136
Gnomad4 FIN exome
AF:
0.0514
Gnomad4 NFE exome
AF:
0.0442
Gnomad4 OTH exome
AF:
0.0839
GnomAD4 genome
AF:
0.117
AC:
17748
AN:
152218
Hom.:
2077
Cov.:
33
AF XY:
0.121
AC XY:
9022
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.214
Gnomad4 AMR
AF:
0.0671
Gnomad4 ASJ
AF:
0.0516
Gnomad4 EAS
AF:
0.602
Gnomad4 SAS
AF:
0.150
Gnomad4 FIN
AF:
0.0499
Gnomad4 NFE
AF:
0.0456
Gnomad4 OTH
AF:
0.0899
Alfa
AF:
0.0618
Hom.:
1649
Bravo
AF:
0.122
TwinsUK
AF:
0.0507
AC:
188
ALSPAC
AF:
0.0410
AC:
158
ESP6500AA
AF:
0.207
AC:
914
ESP6500EA
AF:
0.0416
AC:
358
ExAC
AF:
0.115
AC:
13976
Asia WGS
AF:
0.313
AC:
1088
AN:
3478
EpiCase
AF:
0.0411
EpiControl
AF:
0.0442

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 04, 2013Met2311Val in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 20.7% (914/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs32209). -
Benign, criteria provided, single submitterclinical testingGeneDxNov 13, 2012This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 15, 2013- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 22, 2017Variant summary: The FBN2 c.6931A>G (p.Met2311Val) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in the large control database ExAC at a frequency of 0.1151322 (13966/121304 control chromosomes [2250 homozygotes]), which is approximately 92106 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Congenital contractural arachnodactyly Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 24, 2014This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
18
DANN
Benign
0.90
DEOGEN2
Benign
0.21
T;.;T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.068
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.64
T;.;.
MetaRNN
Benign
0.00015
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.70
N;.;N
MutationTaster
Benign
0.10
P;P
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.45
N;.;N
REVEL
Benign
0.28
Sift
Benign
0.43
T;.;T
Polyphen
0.0
B;.;B
Vest4
0.13
MPC
0.24
ClinPred
0.017
T
GERP RS
5.3
Varity_R
0.085
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs32209; hg19: chr5-127622491; COSMIC: COSV52510041; API